Gene Therapy for HIV
Introduction HIV, or Human Immunodeficiency Virus, is a lentivirus that destroys the immune system by killing CD4+ cells, macrophages, and dendritic cell. The destruction of cells eliminates the immune system, leaving the infected person susceptible to opportunistic diseases and cancers not normally seen in healthy individuals. The progression of the disease leads to AIDS, or acquired immunodeficiency syndrome, which is defined as either a CD4+ count below 200 cells per microliter or the occurrence of rare diseases associated with an HIV infection. HIV can be passed from person to person through semen, vaginal secretions, pre-ejaculate, breast milk, and blood. Without treatment, the average survival time is 9-11 years, however, with many new therapies and medicines, the progression of HIV to AIDS has been slowed down or eliminated while life expectancy has increased (1). Mechanisms of HIV Once the HIV virus enters the body through a bodily secretion, it travels to the lymphoid tissues where helper-T cells mature. Once the virus finds its target cell, the virus uses its envelope protein to interact with the CD4 receptors on the membrane of the T cell. Once the interaction occurs, there is a conformational change that allows the envelope protein to interact with another receptor on the T cell membrane, the chemokine coreceptor (CCR5). The virus then inserts its protein into the membrane, which initiates fusion of the viral envelope and the T cell membrane. This allows the viral genetic material to be inserted into the T cell cytoplasm. At this point, the reverse transcriptase begins its work. Using host nucleotides, the reverse transcriptase transcribes its RNA into single stranded DNA. Next, the reverse transcriptase takes the single stranded DNA it made and reverse transcribes it for a second time to create a double stranded DNA strand. Once the double DNA is fully transcribed, another virus enzyme, integrase, attaches itself to the DNA strand and carries it through a nuclear pore into the nucleus of the T cell. Once inside, it finds the host chromosome, where the integrase makes a nick and inserts the new viral DNA. This action is what establishes life long HIV infections. Once the viral DNA is inserted into the host chromosome, host RNA polymerase makes mRNAs that code for viral proteins. The mRNA then leaves the nucleus and goes through translation, which makes viral proteins the virus needs for the virus to spread. Once translated, the proteins move to the surface of the cell membrane where they are budded off into an envelope enclosed structure. The budded virion is then capable of infecting other cells using the same mechanism. The original host cell creates many virions, keeping the production going (2). Gene Therapy In 2014, researchers successfully engineered an HIV patient's T cells to mimic natural resistance to the HIV virus. To do this, they removed the patient's T cells and modified them using a zinc-finger nuclease (ZFN), which acted as molecular scissors to edit the CCR5 protein. This mutation naturally occurs in about 1% of the population, gifting a natural resistance against the virus. This mutation, whether naturally occurring or engineered, blocks the virus proteins from interacting with the CCR5 proteins, which prevents the virus from entering the T cell. Once modified, the patients are infused with 10 billion of their modified T cells in a single infusion. Within 4 weeks after the infusion, six patients were taken off the antiretroviral drugs completely. One of the patient's HIV virus levels were so low they could not be detected. However, they found that this patient already had one naturally mutated CCR5 protein. The next step in gene therapy is to find a functional cure by using more patients and by modifying more T cells. Although this is still in its experimental phase, there is great potential for suppressing the HIV virus in many patients as well as eliminating the wide assortment of cocktail drugs HIV patients are currently using (3). References 1) HIV/AIDS. Wikipedia. 2) HIV Life Cycle: How HIV Infects a Cell. YouTube. 3) Gene therapy used to block HIV without drugs. Medical News Today.